p38 mitogen activated protein kinase (p38 MAPK) transduces a range of extracellular signals that result in inflammatory response, cell division and differentiation, apoptosis, and cell motility. p38 MAPK was initially believed to be an ideal target for anti-inflammatory therapeutics. However, the failure of more than a dozen chemically different compounds in the clinical phase suggests that p38 MAPK might be a poor therapeutic target. Many of these compounds were found to be hepatotoxic to various degree and tolerance to the anti-inflammatory effect developed within weeks. In hindsight, the failures in clinical trials due to unwanted side effects is perhaps not unexpected as p38 MAPK regulates the activity for more than 60 substrates.
One of the downstream substrates of p38 MAPK is mitogen-activated protein kinase activated protein kinase-2 (MAPKAPK or MK2). Among other roles, MK2 regulates the biosynthesis of tumor necrosis factor α and other cytokines. In addition, MK2 is activated after DNA damage resulting in cell cycle arrest, such that cells have the capacity to repair their DNA and continue to proliferate. MK2 also phosphorylates heat shock 27 (Hsp27), a prominent biomarker of cancer progression. Thus, MK2 could serve as a potential anti-inflammatory target and an anticancer target to improve the efficacy of chemotherapy without the unwanted side effects that affect targets further upstream (i.e., p38 MAPK).
Therefore, there is a continuing need to discover and develop new compounds that inhibit MK2 and that may be useful therapeutics.